Boron containing compounds and their preparation and use in neutron capture therapy

ABSTRACT

The present invention pertains to boron containing thiouracil derivatives, their method of preparations, and their use in the therapy of malignant melanoma using boron neutron capture therapy.

This invention was made with Government support under Contract NumberDE-AC02-76CH00016, between the U.S. Department of Energy and AssociatedUniversities Inc. The Government has certain rights in the invention.

This is a Division of application Ser. No. 660,077 filed Feb. 25, 1991still pending in allowed files.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to new thiourea derivatives of the generalformula ##STR1## wherein: A) R is hydrogen or an alkyl group containingfrom 1 to 8 carbon atoms, provided that where terminal double bondsoriginate from one of the two nitrogen atoms, R and/or the amidehydrogen is replaced;

B) X and X' are selected from the group consisting of ##STR2## standsfor a 1,2-dicarbaborane group, in which the 1- and 2-position of thecarbon atoms correspond to A and B, and where n=0 or 1 but where not atthe same time m, n, and o can all be zero, and where, if n=0, at leastone of the groups R' and R" is a boron-containing group and theremaining groups R' and R" are hydrogen and/or an alkyl group with 1 to8 carbon atoms

and their salts with physiologically compatible organic and inorganicbases or acids.

The present invention also relates to methods for the preparation of thecompounds of formula I, and their application in neutron capture therapyof malignant melanoma.

BACKGROUND OF THE INVENTION

Thioureas are known as substances which accumulate in malignant melanomadue to its active melanin synthesis.

Malignant melanoma is a tumor of melanocytes. Its incidence isespecially high among the fair-skinned population. In most industrialnations its incidence is increasing.

Present treatment of melanoma consists of the surgical removal of theprimary lesion. According to the histologically determined degree ofclassification, skin up to and including the regional lymph nodes areremoved. Despite this, the five-year survival with melanomas grade IIand higher, but also with melanomas grade I with high prognostic index(Kopf, Cancer, 59, 1236, 1987), is poor, as it apparently is notpossible to remove all in-transit metastases of the skin and the lymphnodes.

Radiation treatment of the afflicted limbs, in order to sterilize thesemetastases with or without radical surgery, has not yet been successful(Kynaston, Aust. N.Z. J. Surg., 48, 36, 1978).

The known radiotherapeutic modality of neutron capture therapy utilizesthe property of boron-10 (which represents 20% of the naturallyoccurring nuclide mixture and can be enriched from it) to capture athermal neutron with high probability, as compared to the other nuclidesof the body, and disintegrate upon capture to a helium-4 and a lithium-7particle. Each of these particles is capable of sterilizing a cell witha single event (Gabel, Radiat. Res. 68, 307, 1984).

Depending on the depth of the tumor and the energy spectrum of theneutron beam, at least 14 ppm boron-10 are necessary in the targettissue, for therapy to be successful, with a tumor-to-surrounding ratioof boron of around 10:1 (Fairchild and Bond, Int. J. Radiation Oncol.Biol. Phys., 11, 831, 1985). For a thermal neutron beam and a tumordepth of 4 cm, tumor therapy is not possible with a boron ratio betweentumor and surrounding tissue of 3:1 at any boron concentration; at aratio of 10:1, 36 ppm boron are necessary.

Neutron capture therapy (NCT) differs from other radiotherapy modalitiesinasfar as an external beam produces a high radiation dose only where achemical compound has accumulated prior to irradiation. It differs fromother chemotherapy modalities inasfar as the compound accumulatedexpresses its tumoricidal action only in the field of the beam.

Coderre (Cancer Research 48,6313, 1988) has shown thatp-dihydroxyborylphenylalanine (BPA) can accumulate physiologically inmelanomas. Six hours after intraperitoneal injection, boronconcentration in the tumor of up to 30 ppm were found, with atumor-to-blood and tumor-to-muscle ratio of around 5:1. After 24 hours,boron concentration in the tumor dropped and was too low for therapy.

Mishima (Proc. 1st, Int. Symp. NCT, 355, 1984,) has reported thetreatment of melanoma in swine with neutron irradiation followingperitoneal injection of a total of 10 g BPA.

Boronated thioureas, especially thiouracil derivatives, have beenproposed for NCT by Fairchild (Cancer Res., 42, 5126, 1982). However,except for some attempted syntheses by Wilson (Australia-Japan Workshopon Neutron Capture Therapy for Malignant Melanoma, 1986) no boronatedanalogue has been described in the literature. The major difficulty insynthesizing such derivatives lies in the properties of thedihydroxylboryl group, which is easily cleaved off organic molecules byacids as well as alkali. The dihydroxyboryl group has been introducedinto NCT by Schinazi and Prusoff (Tetrahedron Lett., 50, 4981, 1978; J.Org. Chem., 50, 841, 1985).

The aim of the present invention is to provide stable boron-containingthiourea derivatives for neutron capture therapy, and to give proceduresfor their syntheses.

DETAILED DESCRIPTION OF THE INVENTION

Within the scope of this invention lie all cyclic thiourea derivatives,in which the cyclic portion, aside from the grouping, ##STR3## consistsof carbon, nitrogen, oxygen, sulfur, or combinations of these elements,where the cyclic portion can be saturated or unsaturated, and the numberof the links connecting the two nitrogen atoms of the thiourea fragmentis 2 to 10, in which the carbon and/or nitrogen atoms of the cyclic partcarry hydrogen atoms or where the hydrogen atoms are replaced by alkylgroups with 1 to 8 carbon atoms, and in which the cyclic part containsat least one boron-containing group. The boron containing group can beconnected via a single or several bonds to different atoms of the cyclicpart.

Representative compounds of the present invention include: ##STR4##

The following are the complete chemical names for compounds A-O depictedabove:

(A) 5-dihydroxyboryl-2-thiouracil

(B) 5-dihydroxyboryl-2,4-dithiouracil

(C) 5-dihydroxyboryl-6-propyl-2-thiouracil

(D) 5-dihydroxyboryl-6-propyl-2,4-dithiouracil

(E) 4-(3-carboranylpropyl)-thiyl-pyrimidine-2-thiol

(F) 4-(3-nidocarboranylpropyl)-thiyl-pyrimidine-2-thiol

(G) 5-(N-(3-carboranylpropyl)-N,N-dimethyl)amino-2-thiouracil

(H) 4-dihydroxyboryl-1-methylimidazole-2-thiol

(I) 5-dihydroxyboryl-1-methylimidazole-2-thiol

(K) 4-dihydroxyboryl-5-methyl-1-methylimidazol-2-thiol

(L) 5-dihydroxyboryl-4-methyl-1-methylimidazol-2-thiol

(M) 4-undecahydrododecaboranylthiyl-pyrimidin-2-thiol

(N) 4-undecahydrododecaboranylamino-pyrimidin-2-thiol

(O) 5-carboranylmethyl-1-methyl-2-thio-1,3,4-triazol

(P) 5-nidocarboranylmethyl-1-methyl-2-thio-1,3,4-triazol

(Q) N,N'-thiocarbonyl-1,2-bis(aminomethyl)-nidocarboran.

Of the compounds of the present invention depicted by Formula I above,the most preferred materials are:

5-dihydroxyboryl-2-thiouracil

5-dihydroxyboryl-2,4-dithiouracil

5-dihydroxyborylboryl-6-propyl-2-thiouracil

5-dihydroxyboryl-2,4-dithiouracil

5-dihydroxyboryl-1-methylimidazole-2-thiol and

4-dihydroxyboryl-1-methylimidazole-2-thiol.

Cyclic thioureas according to the present invention can be obtained by:reacting, with boron compounds, a pre-formed cyclic thiourea derivativewith suitable reactive groups, where the thiourea moiety of the endproduct is present as iso-thiourea; by reacting an open-chain thioureamoiety with a suitable boron-containing compound, followed bycyclization to the desired end product; or by reacting a suitable boroncompound with a compound such that the thiourea moiety is introducedduring the formation of the cyclic structure.

More specifically, thiourea derivatives of the general formula ##STR5##wherein R, X, X', m and o are as defined above are prepared when acompound of the general formula ##STR6## wherein R, X, X', m and o areas defined above in which the group(s) R' and R", which are theboron-containing groups in the final product, are the same as in thefinal product, or are present as dialkyloxy boryl groups, preferentiallydiothanolaminoboryl groups, is reacted with a Lewis acid and thedialkoxy groups, when present, are transformed hydrolytically todihydroxyl boryl groups.

In the preparation of iso-thiourea derivatives exemplified by formulaIII above, where at least one of the groups R' and R" are-E-(alkylene)-z, with -E-=-O-, -S-, >NR'", and where R'" is hydrogen oralkyl with C₁ to C₈, and where the alkylene group contains 1 to 8 carbonatoms, and where Z is the 1,2-dicarba-closo-dodecaboranyl or1,2-dicarba-nido-undecaboranyl group, preferably a compound of thegeneral formula III, in which the position(s) that bear(s) the-E-(alkylene)-Z group in the final product, is(are) present as -OH, -SH,or >NR'" H, are reacted with the corresponding1-(omega-haloalkyl)-1,2-dicarba-closo-dodecaborane ##STR7## withhalo=Cl, Br, I and q=1 to 8, under neutral or basic conditions.

The preferred Lewis acids for use in the preparation of the compounds offormula II above include AlBr₃, AlCl₃, and BBr₃.

Thiourea derivatives of the general formula ##STR8## wherein E =-O-,-S-, >NR'", with R'"=H or alkyl with 1 to 8 carbon atoms and p=1 to 8,and Z is the 1,2-dicarba-closo-dodecaboranyl group, are prepared when acompound of the formula ##STR9## wherein E is as defined above isreacted with a 1-(omega-haloalkyl)-1,2-dicarbacloso-dodecarborane of theformula ##STR10## wherein the halogen is Cl, Br or I and p=1 to 8 underneutral or basic conditions.

Thiourea derivatives of the formula ##STR11## wherein R is as definedabove and r=1 to 5 are prepared when a thiosoimicarbazide of the formula##STR12## wherein R is as defined above is reacted with anomega-carboranyl acyl halide of the formula ##STR13## wherein halo and rare as defined above and the reaction product is cyclized by action of abase.

Boron distribution in tissue was measured with5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), and5-dihydroxyboryl-2-thiouracil (BTU) using quantitative neutron captureradiography (Gabel, Cancer Res., 47, 5451, 1987). BTU and BPTU exhibitedseveral advantages compared to the compound p-boronophenylalanine, sofar best suited for accumulation of boron in melanoma: a) BTU and BPTUaccumulate in tumors for long time periods (days to weeks). Fortreatment of tumor it is advantageous if the accumulation once obtainedcan be retained, as several subsequent administrations of the compoundwill lead to higher accumulation. In addition, those cells can be loadedwith boron that were, during the first administration, in a phase oftheir cell cycle not optimal for boron uptake. Also, the time betweenadministration and irradiation can be changed in larger margins. A longperiod of accumulation is essential for a protracted or a fractionatedirradiation; b) BTU and BPTU leave the other non-melanoma organs of thebody rapidly. The compounds leave the body via kidney and gall bladder.Half times of BTU in blood and muscle are around 2 hours, for BTUParound 6 hours. Irradiation can thus be initiated shortly after the lastadministration; c) The compounds of this invention achieve boronconcentration ratios between the tumor and its direct surrounding(blood, muscle, skin) of up to 50:1; and d) Maximum concentrations inthe tumor of 100 ppm boron and more can be achieved.

Tables 1-4 show the distribution of BTU and BPTU in various melanomas.

                  TABLE 1                                                         ______________________________________                                        Distribution of 5-Dihydroxyboryl-2-thiouracil                                 (Compound A) in Harding-Passey Melanoma                                       Dose      Time   Tumor     Ratio Tumor To:                                    (mg/kg)   (hr)   (ppm)     Blood Muscle  Brain                                ______________________________________                                        300       3      40-80     >5    >5      >8                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Distribution of 5-Dihydroxyboryl-6-propyl-2-thiouracil                        (Compound C) in B16 Melanoma                                                  Dose      Time   Tumor     Ratio Tumor To:                                    (mg/kg)   (hr)   (ppm)     Blood Muscle  Brain                                ______________________________________                                        300       12     3-10      >10   approx. approx.                                                               30      20                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Distribution of 5-Dihydroxyboryl-2-thiouracil (Compound A)                    in Balb/cI Mice Carrying Harding-Passey Melanoma                              Dose    Time     Tumor   Ratio Tumor To:                                      (mg/kg) (hr)     (ppm)   Blood   Muscle                                                                              Brain                                  ______________________________________                                        300 (t = 0)                                                                           12       80-100  >5      >8    >15                                    240 (t = 3)                                                                   ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Distribution of 5-Dihydroxyboryl-6-propyl-2-thiouracil                        (Compound C) in C57bl Mice with B16 Melanoma                                  Dose    Time   Tumor       Ratio Tumor To:                                    (mg/kg) (hr)   (ppm)       Blood Muscle  Brain                                ______________________________________                                        190     4      4-90        10    5       4                                                   (mean 41)                                                      ______________________________________                                    

The following examples are to illustrate the invention, especiallyconcerning the procedures according to this invention, and the use ofthe resulting products. In this "carborane" designates the 1,2-dicarba,closo-dodecarborane group, "nidocarborane" the1,2-dicarba-nido-undecaborate group derived from it. In the formulas,"Me" designates a methyl, and "Bz" a benzyl group.

EXAMPLE 1 The Introduction of the Benzylthio Protecting Group a)2-Benzylthio-5-bromo-4-chloropyrimidine (I)

A suspension of 72 g of 0.242 moles (2-benzylthio)-5-bromouracil(Barrett, Goodman and Dittmer, J. Amer. Chem. Soc., 70, 1753, 1948) isrefluxed for 6 hours in 250 ml freshly distilled phosphorus oxychloride.The excess POCl₃ is removed on the rotary evaporator, 250 ml ice waterare added to the residue, and extracted with diethyl ether. The etherlayer is washed with a saturated solution of sodium bicarbonate, driedover magnesium sulfate, and the ether removed on the rotary evaporator.The residue is distilled (170° C., 0.03 mm). Yield 40 g=59%, whitecrystals, Mp 56°-57° C.

b) 2-Benzylthio-5-bromo-4-methoxypyrimidine (II)

A solution of 17 g (0.054 moles) of I in 50 ml dry toluene are addeddropwise to a cooled suspension of 3.25 g (0.06 moles) sodium ethoxide,such that the temperature does not exceed 25° C. Stirring is continuedfor another 2 hours, NaCl is removed by filtering, and toluene isremoved on the rotary evaporator. The residue is purified bydistillation (160° C., 0.03 mm). Yield 13.5 g=80%, white crystals, Mp48°-49° C.

c) 2,4-Bis-(benzylthio)-5-bromopyrimidine (V)

Benzylmercaptane (14.7 ml=0.125 moles) and 3 g (0.13 moles) sodium areheated to 80° C. in 200 ml dry toluene and stirred vigorously for 12-18hours. The resulting thiolate suspension is cooled in an ice bath, and14 g (0.062 moles) 5-bromo-2,4-dichloropyrimidine (Hilbert and Jansen,J. Amer. Chem. Soc., 56, 134, 1934) are added dropwise such that thetemperature does not exceed 25° C. The reaction mixture is stirred atroom temperature overnight, and freed by filtration from NaCl andremaining thiolate. The filtrate is reduced on a rotary evaporator andpurified by distillation (200° C., 0.03 mm). Yield 16.4 g=66%, whitecrystals, Mp 66°-67° C.

EXAMPLE 2 Preparation of Boron-containing Thiourea Derivatives 1a)Diethanolamine derivatives of2-benzylthio-5-dihydroxyboryl-4-methoxypyrimidine (III)

A 250-ml three-necked round-bottom flask, equipped with alow-temperature thermometer and a rubber septum, is flooded withnitrogen gas and then dried thoroughly with a heat gun. II (5 g-16mmoles), dissolved in 150 ml dry, freshly distilled tetrahydrofurane, isinjected into the RB flask through the septum. The solution is cooled to-100° C. in a cooling mixture of ethanol/liquid nitrogen. n-Butyllithium (11 ml=17.5 mmoles) of a 1.6 molar solution in hexane and 5 ml(18.5 mmoles) tributylborate are filled into syringes and cooled to -80°C. in the cooling mixture. n-Butyl lithium is now injected into the RBflask over a period of 5 minutes. The temperature should not rise above-85° C. After 10 additional minutes of stirring, tributyl borate isinjected into the flask. The reaction mixture is allowed to warm to roomtemperature over a period of 1.5 hours, and evaporated on the rotaryevaporator. The residue is dissolved in 100 ml 2M NaOH and is extractedwith 4×50 ml ether. The water layer is brought to pH=2 with concentratedHCl and again extracted with ether. A saturated solution ofdiethanolamine is added to the above ether extract, until no furtherprecipitate is formed. The crystals are filtered and dissolved in littleethanol. Petrol ether (bp 35°-50° C.) is added until a slight cloudinessdevelops. The solution is allowed to stand for 3 hours, the precipitateis filtered off and dried at 100° C. Yield 3.5 g=63.4%, white crystals,Mp 185°-186° C.

b) 5-Dihydroxyboryl-2-thiouracil (A)

Five g (14.5 mmoles) of III are added slowly to a vigorously stirredsolution of 15.5 g (58 mmoles) AlBr₃ in 100 ml dry toluene. The reactionmixture is stirred for 5 hours at 50°-60° C., and cooled. One hundred mlice water are added slowly. The raw product is filtered off, dissolvedin 75 ml 1M NaOH, and the solution extracted with ether. Subsequently,the water layer is acidified to pH=2 with concentrated HCl, theprecipitate is filtered off, and washed with acetone. It isrecrystallized from ethanol. Yield 1.2 g=48.2%, white crystals. Mp>300°C.

Elemental analysis C₄ H₅ BN₂ O₃ S

    ______________________________________                                                     %                                                                             calc.                                                                              found                                                       ______________________________________                                        C              27.94  28.19                                                   H              2.93   3.19                                                    N              16.28  16.21                                                   ______________________________________                                    

2a) Diethanolamine derivative of2,5-bis-(benzylthio)-5-dihydroxyborylpyrimidine (VI)

V [(6.45 g=16 mmoles, 11 ml (17.5 mmoles)] of a 1.6 molar solution ofn-butyl lithium in n-hexane, and 5 ml (18.5 mmoles) tributylborate arereacted according to III. Yield 3.9 g=55.8%, white crystals, Mp157°-158° C.

b) 5-Dihydroxyboryl-2,4-dithiouracil (B)

VI (6.33 g=14.5 mmoles) and 15.5 g (58 mmoles) AlBr₃ are reacted asdescribed for A. The product is dissolved again in 3M NaOH, extractedwith ether, acidified to pH=2 with concentrated HCl, and filtered. Yield1.1 g=40.4%, yellowish crystals, Mp>300° C.

Elemental analysis C₄ H₅ BN₂ O₂ S₂ ×0.5 H₂ O

    ______________________________________                                                     %                                                                             calc.                                                                              found                                                       ______________________________________                                        C              24.49  24.49                                                   H              3.08   2.79                                                    N              14.28  14.38                                                   ______________________________________                                    

5-Dihydroxyboryl-6-propyl-2-thiouracil and5-dihydroxyboryl-6-propyl-2,4-dithiouracil were prepared in an analogousmanner.

3. Synthesis of 4-(3-carboranylpropyl)thlyl-pyrimidine-2-thiol (E)

4-Thiouracil (Mizumo, Ikehara and Watanabe, Chem. Pharm. Bull., 10, 647,1972) in dimethyl formamide is reacted with iodopropyl carborane(Zakharkin, Brattsev and Chapovskii, J. Gen. Chem. USSR, 35, 2149, 1965)to yield 4-(3-carboranylpropyl)thiyl-pyrimidine 2-ol. The chloroderivative is obtained with POCl₃ through methods known in theliterature. Reaction to the 2-thiol derivative with thioureau islikewise achieved through methods known in the literature.

4. Synthesis of 4(5)-dihydroxyboryl-1-methylimidazolo-2-thiol (H/I)

2-Benzylthio-4(5)-iodo-1-methylimidazole is prepared from2-benzylthio-4(5)-iodoimidazole (Hebner and Scholz, U.S. Pat. No.2,654,761, 1951) with dimethyl sulfate. This is reacted intetrahydrofurane at -85° C. with an equimolar amount of butyl lithiumand then tributylborate. Further steps and removal of the benzylprotecting group is carried out in analogy to5-dihydroxyboryl-2-thiouracil.

5. Synthesis of 4-undecahydrododecaboranylamino-pyrimidine 2-thiol (N)

2-Benzylthio-4-chloropyrimidine is reacted in DMF with sodiumaminoundecahydrododecaborate (Nakagawa and Aono., Chem. Pharm. Bull.,24, 778, 1976). Removal of the benzyl group is achieved as described for5-dihydroxyboryl-2-thiouracil.

In an analagous manner, 4-undecahydrododecaboranylthio pyrimidine2-thiol is obtained upon reaction with disodiummercaptoundecahydrododecaborate.

6. Synthesis of 5-nidocarboranylmethyl-1-methyl-2-thio-1,3,4-triazol (P)

N-Methyl-thiosemicarbazide is reacted with 3-carboranyl acetyl chloride(Zakharkin, Chapovskii, Brattsev and Stanko, J. Gen. Chem. USSR, 36,892, 1966) to N-methyl-N"-B-carboranyl acetyl thiosemicarbazine. Thereaction product is cyclized with NaOH analogous to Kroger, Sattler andBeyer (Ann. Chem., 643, 128, 1961).

7. Synthesis of N,N'-thiocarbonyl-1,2-bis-(aminomethyl)-nidocarborane(O)

1,2-Bis-(aminomethyl)-nidocarborane (Zakharkin and Grebennikov, Izv.Akad. Nauk SSSR, Ser. Khim. 2019, 1966) is heated slowly with carbondisulfide in 50% ethanol/water under nitrogen according to Chau-Der Li,Mella and Sartorelli (J. Med. Chem., 24, 1989, 1981). After 1 hour, anequimolar amount of concentrated HCl is added, and the reaction mixtureis worked up after refluxing overnight.

EXAMPLE 3 Examples of Use 1. Preparation of a solution of5-dihydroxyboryl-2-thiouracil for intraperitoneal injection

5-Dihydroxyboryl-2-thiouracil (50.4 mg) are dissolved in 10 ml 0.12MNaOH and adjusted to pH=7.8 with 0.12 m HCl. The solution is sterilefiltered.

2Preparation of an orally administrable form

a) Five hundred mg 5-dihydroxyboryl-2-thiouracil are dissolved in 10 ml1M tris-hydroxymethylaminomethane.

b) Mannitol (4.5 g) and 2 g methyl hydroxyethyl cellulose are mixed forapproximately 3 minutes, passed through a sieve of a mesh diameter of0.8 mm, and mixed again for 3 minutes. The obtained powder is wettedwith the solution a) and mixed. The humid granulate is passed through asieve with a mesh diameter of 1.25 mm, dried for 2 hours at 50° C. and27 kPa (200 torr), passed through a sieve with a mesh diameter of 1.0mm, and mixed for three minutes. The granulate obtained is mixed with100 ml water p.i. and used within 5 minutes after preparation.

3. Use of the Compound

Balb/c mice, carrying a subcutaneously transplanted Harding-Passeymelanoma on their hind leg, are injected intraperitoneally 5 times, with6 hour intervals, with the solution prepared according to Example 3paragraph 1 above. The uptake in tumor is determined to 15-30 ppm withquantitative neutron capture radiography. The tumor is irradiated oncewith a neutron beam from a reactor, while the rest of the body isprotected from thermal neutron by lithium fluoride embedded in epoxyresin. The growth of the tumor is measured daily over the course ofseveral weeks. With a neutron dose of 8 MW×min at the Medical ResearchReactor at Brookhaven National Laboratory, it is found that the tumordoes not grow in around half of the group treated; in the other half,tumor growth is observed only after 7 to 10 weeks. In the absence ofboron, retardation of tumor growth is found only in the first threeweeks after irradiation.

I claim:
 1. A compound of the formula ##STR14## wherein R' is alkylhaving 1 to 7 carbon atoms or hydrogen; R" is hydrogen, alkyl having 1to 7 carbon atoms, dihydroxyboryl, or alkylcarboranyl wherein the alkylgroup has 1 to 7 carbon atoms, provided that one R" must be a boroncontaining group and the other R" must be hydrogen or alkyl and theirsalts with physiologically compatible organic and inorganic bases oracids.
 2. 4-dihydroxyboryl-5-methyl-1-methylimidazol-2-thiol. 3.5-dihydroxyboryl-4-methyl-1-methylimidazol-2-thiol. 4.N,N'-thiocarbonyl-1,2-bis(aminoethyl)-nidocarboran. 5.5-dihydroxyboryl-1-methylimidazole-2-thiol. 6.4-dihydroxyboryl-1-methylimidazole-2-thiol.